Increased expression of secreted frizzled-related protein 4 in polycystic kidneys.
Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary disease associated with progressive renal failure. Although cyst growth and compression of surrounding tissue may account for some loss of renal tissue, the other factors contributing to the progressive renal failure in patients with ADPKD are incompletely understood. Here, we report that secreted frizzled-related protein 4 (sFRP4) is upregulated in human ADPKD and in four different animal models of PKD, suggesting that sFRP4 expression is triggered by a common mechanism that underlies cyst formation. Cyst fluid from ADPKD kidneys activated the sFRP4 promoter and induced production of sFRP4 protein in renal tubular epithelial cell lines. Antagonism of the vasopressin 2 receptor blocked both promoter activity and tubular sFRP4 expression. In addition, sFRP4 selectively influenced members of the canonical Wnt signaling cascade and promoted cystogenesis of the zebrafish pronephros. sFRP4 was detected in the urine of both patients and animals with PKD, suggesting that sFRP4 may be a potential biomarker for monitoring the progression of ADPKD. Taken together, these observations suggest a potential role for SFRP4 in the pathogenesis of ADPKD.
Romaker
Daniel
D
Renal Division, University Hospital Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany.
Puetz
Michael
M
Teschner
Sven
S
Donauer
Johannes
J
Geyer
Marcel
M
Gerke
Peter
P
Rumberger
Brigitta
B
Dworniczak
Bernd
B
Pennekamp
Petra
P
Buchholz
Björn
B
Neumann
H P H
HP
Kumar
Rajiv
R
Gloy
Joachim
J
Eckardt
Kai-Uwe
KU
Walz
Gerd
G
D000818:Animals; D002478:Cells, Cultured; D020420:Cyst Fluid / Q000502:physiology; D004195:Disease Models, Animal; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009399:Nephrons / Q000196:embryology; D007690:Polycystic Kidney Diseases / Q000378:metabolism; D016891:Polycystic Kidney, Autosomal Dominant / Q000209:etiology* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000502:physiology*; D015398:Signal Transduction; D013141:Spiro Compounds / Q000494:pharmacology; D050396:TRPP Cation Channels / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology; D051153:Wnt Proteins / Q000502:physiology; D014981:Xenopus; D015027:Zebrafish; D000094742:Secreted Frizzled-Related Proteins
D009025:Morpholines; D011518:Proto-Oncogene Proteins; D013141:Spiro Compounds; D050396:TRPP Cation Channels; D014157:Transcription Factors; D051153:Wnt Proteins; C491947:Invs protein, mouse; C118723:SFRP4 protein, human; D000094742:Secreted Frizzled-Related Proteins; C103281:satavaptan